Investigating the role of the microbiome and inflammation in acute and chronic pain in patients with sickle cell disease

研究微生物组和炎症在镰状细胞病患者急性和慢性疼痛中的作用

• 批准号: 9769125
• 负责人: Amanda M Brandow
• 金额: $ 75.68万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9769125
• 关键词: Absence of pain sensation; Accident and Emergency department; Acute; Acute Pain; Adolescent; Adult; Affect; Age; Bacterial Translocation; Biological Assay; Biological Factors; Biology; Blood; Cells; Chronic; Chronic Fatigue Syndrome; Clinical Research; Complex Regional Pain Syndromes; Complication; Data; Development; Disease; Emergency department visit; Feces; Frequencies; Gender; Genes; Genetic Transcription; Goals; Health; Health Care Costs; Hemolysis; Hospitalization; Immune system; Immunologic Receptors; Impairment; Incidence; Inflammation; Inflammatory; Inflammatory Response; Inherited; Inpatients; Intestines; Irritable Bowel Syndrome; Knowledge; Lead; Ligation; Lipopolysaccharides; Measures; Migraine; Modeling; Nervous system structure; Nociceptors; Opioid; Outcome; Pain; Pain management; Patient Outcomes Assessments; Patients; Pattern recognition receptor; Peripheral; Plasma; Play; Population; Quality of life; Race; Recombinant DNA; Recurrence; Reperfusion Injury; Reporter; Research; Rheumatoid Arthritis; Role; Severities; Siblings; Sickle Cell; Sickle Cell Anemia; TLR4 gene; Testing; Vertebral column; Work; base; care seeking; chemokine; chemotherapy; chronic pain; chronic pelvic pain; clinical phenotype; cytokine; daily pain; dysbiosis; effective therapy; gut microbiota; immunoregulation; improved; inflammatory milieu; microbial; microbiome; microbiota; microorganism antigen; multidisciplinary; novel; opioid sparing; peripheral pain; response; sickling; side effect; social stigma; targeted treatment

PROJECT SUMMARY/ABSTRACT The overall goals of the proposed work are to investigate the role of the microbiome and inflammation in acute and chronic pain in patients with sickle cell disease (SCD). Intermittent, excruciating acute pain accounts for the majority of emergency department visits and hospitalizations for patients with SCD and the frequency of these episodes increase with age. Chronic, debilitating, daily pain also occurs in ~40% of adolescents and adults with SCD and the incidence and severity of chronic pain also increases with age. A critical knowledge gap exists in the identification of reasons other than chronic sickling that contribute to the unpredictable clinical phenotype of frequent acute and chronic daily pain. Opioids are the backbone treatment for both acute and chronic SCD pain; however they often provide ineffective analgesia and can lead to significant side effects and stigma. An increased understanding of the biology of acute and chronic SCD pain is needed in order to develop opioid-sparing, targeted therapies to improve the quality of life of patients with SCD. Alterations in the intestinal microbiota or dysbiosis, a known driver of chronic inflammation, have not been explored in SCD but play a role in other chronic inflammatory diseases and pain-related disorders. Dysbiosis has been associated with pain in rheumatoid arthritis, migraines, chronic pelvic pain and chemotherapy-induced pain. Dysbiosis can lead to a “leaky” intestinal barrier resulting in bacterial translocation into the blood. Bacterial translocation (i.e., systemic microbial antigen exposure) can trigger chronic inflammation which can sensitize peripheral pain nociceptors and result in recurrent acute and chronic pain. Immune regulation of this inflammatory response can modulate the inflammatory impact on pain. Nervous system sensitization occurs in SCD patients. However, the biologic factors that lead to nervous system sensitization in SCD are unknown. Thus, investigating the connection between the microbiome, inflammation and SCD pain is important. In this proposal, we will investigate whether microbial antigens from intestinal microbiota alterations drive inflammation and pain in patients with SCD. The following aims are proposed: 1) Examine the relationship between systemic microbial antigen levels, intestinal microbiota composition and diversity and the systemic inflammatory state in patients with SCD and healthy race-matched controls and 2) Investigate whether acute and chronic pain in SCD patients is associated with increases in systemic microbial antigen exposure and an elevated inflammatory state. Our collaborative and multidisciplinary team has clinical and research expertise in SCD pain biology, inflammation, microbiome and SCD patient-reported outcomes. We will utilize a multifaceted approach to investigate how microbial exposure and host inflammatory response impacts the expression of SCD pain. Our work has the potential to identify targets for novel opioid-sparing pain treatments that will decrease patient suffering.

项目概要/摘要 拟议工作的总体目标是研究微生物组和炎症在急性发作中的作用 镰状细胞病 (SCD) 患者的慢性疼痛是间歇性的、难以忍受的急性疼痛。 大多数 SCD 患者急诊就诊和住院的频率以及 这些症状随着年龄的增长而增加，慢性、使人衰弱的日常疼痛也发生在约 40% 的青少年和青少年身上。 患有 SCD 的成年人，慢性疼痛的发生率和严重程度也会随着年龄的增长而增加。 除了慢性镰状细胞病之外，在识别导致不可预测的临床症状的原因方面存在差距 频繁的急性和慢性日常疼痛的表型阿片类药物是急性和慢性疼痛的主要治疗方法。 慢性 SCD 疼痛；然而，它们通常无法有效镇痛，并可能导致严重的副作用和 需要加深对急性和慢性 SCD 疼痛生物学的了解，以便 开发节省阿片类药物的靶向疗法，以改善 SCD 患者的生活质量。 肠道微生物群或生态失调是慢性炎症的已知驱动因素，尚未在 SCD 中进行探索，但 在其他慢性炎症疾病和疼痛相关疾病中发挥作用。 类风湿性关节炎、偏头痛、慢性骨盆痛和化疗引起的菌群失调引起的疼痛。 导致肠道屏障“渗漏”，导致细菌易位到血液中（即， 全身微生物抗原暴露）会引发慢性炎症，从而使周围疼痛变得敏感 伤害感受器并导致反复发生的急性和慢性疼痛。免疫调节这种炎症反应。 可以调节 SCD 患者发生的炎症对疼痛的影响。 然而，导致 SCD 神经系统敏感的生物学因素尚不清楚。 研究微生物群、炎症和 SCD 疼痛之间的联系非常重要。 建议，我们将研究肠道微生物群改变的微生物抗原是否驱动 提出以下目标： 1) 检查 SCD 患者的炎症和疼痛之间的关系。 全身微生物抗原水平、肠道微生物群组成和多样性与全身微生物之间的关系 SCD 患者和健康种族匹配对照患者的炎症状态，2) 调查是否急性 SCD 患者的慢性疼痛与全身微生物抗原暴露的增加和 我们的协作和多学科团队拥有以下方面的临床和研究专业知识。 SCD 疼痛生物学、炎症、微生物组和 SCD 患者报告的结果我们将利用多方面的结果。 研究微生物暴露和宿主炎症反应如何影响表达的方法 我们的工作有可能确定新型阿片类药物缓解疼痛治疗的靶点，这些治疗方法将 减少患者痛苦。